Useful procedure for the synthesis of pincer-type heterodentate azomethine ligands bearing multiple functionalities

Article abstract of DOI:10.1055/s-2007-965990

A simple and efficient synthetic protocol is developed for the preparation of heterodentate azomethine ligands bearing various functionalities, by Schiff condensation of dialdehydes with monoprotected diamine followed by reduction of the azomethine bond a

Full text of DOI:10.1055/s-2007-965990

PAPER
1169
Useful Procedure for the Synthesis of Pincer-Type Heterodentate Azomethine
Ligands Bearing Multiple Functionalities
S
ynthesis of Pince
a
r-Type
H
ete
t
rodent
a
ate Azome
t
l
hines iya E. Borisova,* Marina D. Reshetova, Maxim V. Kuznetcov, Yuri A. Ustynyuk
Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1/3, 119992 Moscow, Russian Federation
Fax +7(495)9392677; E-mail: Borisova.Nataliya@gmail.com
Received 12 December 2006; revised 19 February 2007
Logically, if monoprotected aromatic diamines are used
Abstract: A simple and efficient synthetic protocol is developed
instead of aliphatic analogues at the stage of condensation
with diformyls (Scheme 1), it will open a straightforward
access to potentially very useful macrocyclic azometh-
for the preparation of heterodentate azomethine ligands bearing var-
ious functionalities, by Schiff condensation of dialdehydes with
monoprotected diamine followed by reduction of the azomethine
bond and deprotection. The efficient procedure of obtaining N-tert- ines. Actually, in some preliminary investigations we ob-
butoxycarbonyl-protected o-phenylenediamine in large scale is also
elaborated.
served that reaction of N-acetyl-o-phenylenediamine with
diformylphenol 1a in methanol smoothly led to 2:1-con-
densation product 3 which upon reduction with NaBH4
gave the protected pincer diamine 4 in good overall yield
(Scheme 2). Unfortunately numerous attempts to depro-
tect diamine 4 failed to be effective due to the unexpect-
Key words: Schiff bases, aromatic diamines, cyclizations, macro-
cycles, regioselectivity, heteropolydentate ligand
Pincer-type polyamines containing various functionalities edly high stability of amide bonds under both acidic and
are an important class of compounds in organic synthesis. basic conditions. Thus, this paper describes a simple and
They are of particular interest as useful building blocks short procedure of obtaining pincer-type enlarged aromat-
for creating macrocyclic azomethines, which have found ic diamines useful for further macrocyclic synthesis.
applications spanning from supramolecular recognition of
metal ions,1 anions,2 and neutral molecules3 to medical
t-Bu
uses.4
NH2
Generally, construction of macrocyclic azomethines im-
plies ‘fragment-to-fragment’ assembling5,6 (Scheme 1).
NHAc
O
OH
O
With this methodology, i.e., by condensation of prelimi-
nary monoprotected flexible aliphatic diamines with di-
carbonyls 1 followed by reduction and deprotection, a
number of macrocyclic derivatives 2 have been efficiently
synthesized.6 Unfortunately, due to the absence of suffi-
cient conformational rigidity, the above type of macrocy-
cles is not capable of acting as core of choice for selective
supramolecular recognition.6 Although the required level
of conformational rigidity can be achieved by substituting
aliphatic diamine units with aromatic analogues,2c no gen-
eral method for obtaining macrocyclic azomethines bear-
ing aromatic diamine units has been developed.
1a
MeOH, r.t., 12 h
t-Bu
t-Bu
NaBH4
MeOH, 3 h, ∆
NH OH HN
N
OH
N
NHAc AcHN
NHAc AcHN
3 (98%)
4 (84%)
Scheme 2
R
NH2
The initial phase of our project required facile access to
multigram quantities of N-tert-butoxycarbonyl-protected
o-phenylenediamine 5. The use of the latter building
block for supramolecular chemistry was reported.7 The
traditional method for obtaining this useful block7b im-
plies treatment of o-phenylenediamine with Boc-ON by
utilizing large quantities of flammable solvents and carry-
ing out the reaction by prolonged heating under anaerobic
conditions.7b We proposed that substitution of Boc-ON
with a more active Boc donor (e.g. Boc2O) could make it
possible to carry out the procedure under milder condi-
tions. In support of this, Tamura et al. reported on the syn-
H2N
O
O
NH HN
R
1
X
X
X
X
NH
PG
HN
PG
N
N
R'
2
Scheme 1
SYNTHESIS 2007, No. 8, pp 1169–1174
Advanced online publication: 23.03.2007
DOI: 10.1055/s-2007-965990; Art ID: T17906SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7
thesis of
5 using Boc2O. Unfortunately, neither
experimental details nor the yield of target product were

1170
N. E. Borisova et al.
PAPER
described.8a Heydari et al. reported the preparation of
monoprotected diamine 5 in 80% yield by use of Boc2O/
LiClO4 system, the reaction was carried out by stirring for
five hours.8b In our hands, the use of Boc2O allowed to re-
duce the reaction time down to ten minutes without neces-
sity of exploring inert atmosphere, large volumes of
flammable solvents and prolonged heating. Moreover,
Boc2O acts as efficient reagent at r.t. even when large
quantities (45–75 g) of o-phenylenediamine were loaded
and only subsequent crystallization was required to obtain
pure monoprotected diamine 5 in satisfactory (69%) yield.
Table 1 Stepwise Synthesis of Diamine Blocks 9
Dialdehyde
Yield of 6 (%)a Yield of 8 (%)a Yield of 9 (%)a
1a
1b
1c
1d
1e
1f
70
98
98b
76
95
90
75
–
77
74c
71
80
–
70c
10c
–
d
–
–
–
With a facile access to 5 in hand, a comparative study of
obtaining Schiff bases 6 became real. In order to investi-
gate the influence of electronic properties and topology of
dicarbonyl compounds on the efficacy of Schiff base for-
mation, a series of dicarbonyl derivatives was examined
(Scheme 3, Tables 1 and 2). We chose to utilize 1b which
was expected to give good yield of Schiff base due to elec-
tron-withdrawing properties of pyridine nucleus. We also
chose superaromatic pyrrolic derivatives 1c, 1e and 1f
which are known to form azomethines in low yields as
well as their geometrical analogs, furan derivatives 1d,
1g, slightly exhibiting superaromaticity. 2,6-Diformyl-4-
tert-butylphenol (1a) was selected by us as a model dicar-
bonyl derivative routinely used in obtaining Schiff
bases.1,5a,6b
e
1g
–
–
a Yields refer to isolated products.
b Compound 8b could be alternatively produced by reacting 2,6-
bis(tosyloxymethyl)pyridine with N-tert-butoxycarbonyl-o-phe-
nylenediamine.9
c Acid catalyst (TsOH, 0.1–0.3 molar equiv) is required.
d No 8e was detected in the reaction mixture when the general proce-
dure was used.
e No trace amounts of 6g were isolated in the presence of TsOH, the
only product (90%) being 7g.
pyrrolic derivatives 1c, 1e, and 1f, acid catalyst (TsOH)
was needed for obtaining the target products 6 in reason-
able yields. In the absence of TsOH no target Schiff bases
were isolated, the only result being 1:1 condensation
products 7 (Figure 1) or a mixture of the corresponding
Schiff bases 6 and 7.
R
NH2
R
N
N
NH
O
O
HN
NH
R
N
O
1
5
Boc
Boc
Boc
6
NH
1b
N
Boc
7
Me Me
O
O
Pr
Pr
Figure 1 1:1 Condensation product 7
1f
1c
N
N
N
H
H
H
O
O
In general, the efficacy of Schiff base formation correlates
well with the electronic properties of the starting di-
formyls. When superaromatic diformylpyrroles 1c, 1e,
and 1f were used, acid catalyst was required to obtain the
target Schiff bases, whereas furan analogue 1d readily
gave the desired 6d in 71% yield without necessity of us-
ing catalyst. Surprisingly, only 1:1 condensation was ob-
served when thiodiformylfuran derivative 1g was used.
We still cannot rationally explain this phenomenon.
O
O
1d
1e
O
1g
O
O
O
O
S
O
O
N
N
H
O
O
H
Scheme 3
To prepare tert-butoxycarbonyl protected amines, an effi-
cient reduction of both azomethine bonds of Schiff bases
6 was required. We found that brief treatment of aldimines
6 with sodium borohydride in anhydrous methanol at
room temperature gave the desired amines 8 in excellent
yields (Scheme 4, Tables 1 and 2) whereas the use of tra-
ditional conditions (–30 °C) led to extensive degradation
of target compounds. Unfortunately, we did not succeed
in preparing even an analytical sample of dipyrrolic deriv-
ative 8f due to its instability.
In order to optimize the procedure of producing Schiff
bases 6, a broad variety of conditions was attempted. The
best results were obtained when the reaction was carried
out under mild conditions due to the possibility of sup-
pressing thermal and oxidative degradation of starting di-
aldehydes. Thus, good yields of Schiff bases were
obtained when condensations were performed by simple
stirring of concentrated methanol solutions at room tem-
perature for at least four hours (Scheme 3, Tables 1
and 2). In the cases of the slightly less reactive a-formyl
Synthesis 2007, No. 8, 1169–1174 © Thieme Stuttgart · New York

PAPER
Synthesis of Pincer-Type Heterodentate Azomethines
1171
Table 2 Spectroscopic Data for Compounds 3, 4, 6, 8, and 9
Product
IR (mull)
1H NMR (400 MHz, CDCl3/TMS)
d, J (Hz)
13C NMR (100 MHz, CDCl3/TMS)
d
3a,b
1668 (C=O), 1622
13.51 (s, 1 H, OH), 9.04 (s, 2 H, CH=N), 8.98 (br 167.88 (C=N), 159.42 (C=O), 141.96 (Carom),
(C=N), 3172 (OH), 3321 s, 2 H, NH), 8.25 (d, J = 7.2, 2 Harom), 8.19 (s, 2 139.85 (Carom), 135.96 (CHarom), 133.41 (Carom),
and 3390 (NH) Harom), 7.34 (d, J = 7.8, 2 Harom), 7.28 (t, J = 7.8, 130.97 (CHarom), 127.17 (CHarom), 124.24
2 Harom), 7.17 (t, J = 7.2, 2 Harom), 2.17 (s, 6 H,
CH3), 1.42 (s, 9 H, t-C4H9)
(CHarom), 121.68 (CHarom), 121.31 (CHarom),
117.86 (Carom), 34.04 (C), 30.05 (CH3), 23.50
(CH3)
4c,d
1680 (C=O), 3340 (NH, 9.91 (br s, 1 H, OH), 7.75 (d, J = 5.7, 2 Harom),
152.15 (C=O), 143.76 (CarOH), 132.13 (Carom),
OH)
7.71 (d, J = 6.0, 2 Harom), 7.47 (t, J = 5.7, 2 Harom), 130.18 (CHarom), 127.67 (Carom), 126.09 (Carom),
7.38 (t, J = 6.0, 2 Harom), 7.29 (s, 2 H, NH), 5.69 125.50 (Carom), 124.32 (CHarom), 114.16 (CHarom),
(s, 4 H, NH2), 2.92 (s, 6 H, CH3), 1.12 (s, 9 H, t- 113.63 (CHarom), 45.44 (CH2), 34.23 (C), 31.38
C4H9)
(CH3) 23.37 (CH3)
6ac,e
3385 (OH, NH), 1728
(C=O), 1685 (C=N),
1630 (C=NH)
13.85 (s, 1 H, OH), 8.97 (s, 2 H, NH), 8.56 (s, 2 159.61 (C=N), 154.35 (C=O), 153.24 (Carom),
H, HC=N), 8.09 (s, 2 Harom), 7.67 (d, J = 7.6, 2 141.58 (Carom), 141.33 (CHarom), 133.13 (Carom),
Harom), 7.31 (t, J = 7.6, 2 Harom), 7.25 (d, J = 7.6, 130.86 (CHarom), 127.44 (CHarom), 124.93
2 Harom), 7. 18 (t, J = 7.6, 2 Harom), 1.43 (s, 18 H, (CHarom), 122.58 (CHarom), 121.72 (CHarom),
t-C4H9O), 1.36 (s, 9 H, t-C4H9)
118.66 (Carom), 79.61 (C), 34.21 (C), 31.43 (CH3),
28.42 (CH3)
6bc,f
3390 (NH), 1710 (C=O), 8.72 (s, 2 H, NH), 8.40 (s, 2 H, HC=N), 8.37 (d, 159.87 (C=N), 154.52 (C=O), 139.77 (Carom),
1610 (C=N), 1595
(CHarom
J = 8.0, 2 Harom), 8.18 (t, J = 8.0, 1 Harom), 7.91 (d, 138.40 (Carom), 133.75 (Carom), 128.23 (CHarom),
J = 8.0, 2 Harom), 7.40 (d, J = 7.6, 2 Harom), 7.29 (t, 124.03 (CHarom), 123.95 (CHarom), 120.52
J = 8.0, 2 Harom), 7. 12 (t, J = 7.6, 2 Harom), 1.47 (s, (CHarom), 119.45 (CHarom), 118.31 (CHarom),
)
18 H, t-C4H9O)
80.01 (C), 28.45 (CH3)
6c
3400 (NH), 3310 (NH), 10.28 (br s, 1 H, NH), 8.37 (s, 2 H, HC=N), 8.22 152.71 (C=O), 148.35 (C=N), 138.18 (Carom),
1730 (C=O), 1653
(C=N)
(d, J = 8.0, 2 Harom), 7.69 (s, 2 H, NH), 7.25 (t,
J = 8.0, 2 Harom), 7.06 (d, J = 7.6, 2 Harom), 6.99 (t, 122.56 (CHarom), 118.25 (CHarom), 117.34
J = 7.6, 2 Harom), 6.82 (s, 2 Harom), 1.55 (s, 18 H, (CHarom), 116.88 (CHarom), 80.64 (C), 28.35
134.69 (Carom), 133.67 (Carom), 127.57 (CHarom),
t-C4H9O).
(CH3)
6d
3395 (NH), 1730 (C=O), 8.49 (s, 2 H, HC=N), 8.25 (d, J = 8.3, 2 Harom),
154.28 (C=O), 152.52 (C=N), 147.51 (Carom),
1620 (C=N), 1593
(CHarom
7.88 (s, 2 H, NH), 7.28 (t, J = 8.3, 2 Harom), 7.24 138.95 (Carom), 134.10 (Carom), 128.03 (CHarom),
)
(s, 2 Harom), 7.17 (d, J = 7.8, 2 Harom), 7.03 (t,
J = 7.8, 2 Harom), 1.56 (s, 18 H, t-C4H9O)
123.51 (CHarom), 119.10 (CHarom), 119.02
(CHarom), 117.68 (CHarom), 79.98 (C), 28.15
(CH3)
6ec
3380 (NH), 3216 (NH), 10.65 (br s, 2 H, NH), 8.03 (s, 2 H, HC=N), 7.96 152.71 (C=O), 150.39 (C=N), 146.33 (Carom),
1729 (C=O), 1619
(C=N)
(d, J = 7.5, 2 Harom), 7.67 (br s, 2 H, NH), 7.14 (d, 138.51 (Carom), 133.91 (Carom), 130.34 (CHarom),
J = 7.1, 2 Harom), 7.06 (t, J = 7.5, 2 Harom), 6.97 (t, 126.44 (CHarom), 122.15 (CHarom), 119.77
J = 7.1, 2 Harom), 6.59 (br s, 2 Harom), 6.01 (br s, 2 (CHarom), 119.38 (CHarom), 118.38 (CHarom),
Harom), 2.76 (s, 6 H, CH3), 0.94 (s, 18 H, t-C4H9O) 108.05 (Carom), 79.86 (C), 50.22 (C), 36.26 (CH3),
27.42 (CH3)
6fg
3482 (NH), 3380 (NH), 9.28 (br s, 2 H, NH), 8.35 (s, 2 H, HC=N), 8.12
152.53 (C=O), 146.05 (C=N), 133.43 (Carom),
132.59 (Carom), 127.90 (CHarom), 126.43 (CHarom),
122.31 (CHarom), 118.63 (CHarom), 117.62 (Carom),
1723 (C=O), 1610
(d, J = 7.6, 2 Harom), 7.75 (s, 2 H, NH), 7.21 (t,
J = 7.6, 2 Harom), 7.3–6.8 (m, 4 Harom), 2.66 (t,
(C=N), 1580 (CHarom
)
J = 7.8, 4 H, CH2), 2.19 (s, 6 H, CH3), 1.64 (dd, 116.38 (Carom), 80.21 (C), 28.26 (CH3), 25.99
J = 8.0, 7.8, 4 H, CH2), 1.48 (s, 18 H, t-C4H9O), (CH2), 24.69 (CH3), 13.94 (CH2), 10.12 (CH3)
1.02 (t, J = 8.0, 6 H, CH3)
8ah
8b
3330 (NH), 1700 (C=O), 8.76 (br s, 1 H, OH), 7.36 (d, J = 6.8, 2 H, CHar), 154.11 (C=O), 152.81 (COH), 142.43, (Carom
1605 (CHarom 7.21 (s, 2 Harom), 7.11 (t, J = 7.6, 2 Harom), 7.0–6.7 141.31 (Carom), 126.27 (CHarom), 125.59 (CHarom),
(m, 4 Harom), 6.36 (br s, 2 H, NH), 4.37 (s, 4 H, 124.80 (CHarom), 123.73 (Carom), 119.83 (CHarom),
)
)
CH2), 1.50 (s, 18 H, t-C4H9), 1.32 (s, 9 H, t-C4H9). 114.72 (CHarom), 80.55 (C), 46.74 (CH2), 34.05
(C), 31.52 (CH3), 28.25 (CH3)
3423, 3325 (NH), 1695
(C=O), 1595 (CHarom
7.56 (t, J = 7.6, 1 Harom), 7.29 (d, J = 7.2, 2 Harom), 157.41 (C=O), 142.45 (Carom), 137.26 (Carom),
)
7.16 (d, J = 7.6, 2 Harom), 7.063 (t, J = 7.6, 2
126.90 (CHarom), 126.10 (CHarom), 124.22 (Carom),
Harom), 6.73 (t, J = 7.2, 2 Harom), 6.67 (d, J = 7.6, 2 120.16 (CHarom), 117.89 (CHarom), 112.70
Harom), 4.45 (s, 4 H), 1.43 (s, 18 H)
(CHarom), 80.57 (C), 49.13 (CH2), 28.32 (CH3)
Synthesis 2007, No. 8, 1169–1174 © Thieme Stuttgart · New York

1172
N. E. Borisova et al.
PAPER
Table 2 Spectroscopic Data for Compounds 3, 4, 6, 8, and 9 (continued)
Product
IR (mull)
–
1H NMR (400 MHz, CDCl3/TMS)
d, J (Hz)
13C NMR (100 MHz, CDCl3/TMS)
d
8d
7.33 (d, J = 7.6, 2 Harom), 7.05 (t, J = 7.6, 2 Harom), 151.99 (C=O), 126.19 (Carom), 124.86 (Carom),
6.8–6.5 (m, 4 Harom), 6.39 (br s, 2 H, NH), 6.13 (s, 122.38 (Carom), 118.83 (CHarom), 116.51 (CHarom),
2 Harom), 4.22 (s, 4 H, CH2), 1.49 (s, 18 H, t-
113.27 (CHarom), 109.84 (CHarom), 107.91
C4H9O)
(CHarom), 80.47 (C), 41.74 (CH2), 28.33 (CH3)
9ai
9b
3320 (NH2, NH), 1600
7.23 (s, 2 Harom), 7.1–6.7 (m, 8 Harom), 4.39 (s, 4 153.65 (COH), 135.49 (Carom), 125.85 (CHarom
H, CH2), 1.32 (s, 9 H, CH3) Carom), 123.76 (Carom), 120.44 (CHarom), 116.48
,
(CHarom
)
(CHarom), 113.93 (CHarom), 110.74 (CHarom),
46.80 (CH2), 34.21 (C), 31.50 (CH3)
3360 (NH2, NH), 1595,
1578 (CHarom
7.52 (t, J = 7.6, 1 Harom), 7.17 (d, J = 7.6, 2 Harom), 157.71 (C), 137.38 (CHarom), 133.74 (Carom),
)
6.78 (td, J = 7.6, 1.6, 2 Harom), 6.73 (dd,
J = 7.6, 1.6, 2 Harom), 6.66 (td, J = 7.6, 1.3, 2
121.04 (CHarom), 120.31 (CHarom), 118.96
(CHarom), 117.02 (CHarom), 112.44 (CHarom),
Harom), 6.62 (dd, J = 7.6, 1.3, 2 Harom), 4.43 (s, 4 49.39 (CH2)
H, CH2), 4.25 (br s, 6 H, NH2, NH)
9d
–
6.81 (td, J = 7.6, 1.5, 2 H, CH), 6.76 (dd,
J = 7.6, 1.5, 2 H, CH), 6.70 (dd, J = 7.6, 1.2, 2 H, 121.03 (CHarom), 120.30 (CHarom), 118.95
CH), 6.66 (td, J = 7.6, 1.2, 2 H, CH), 6.12 (s, 2 H, (CHarom), 117.00 (CHarom), 112.42 (CHarom),
157.71 (Carom), 137.37 (Carom), 133.73 (Carom),
CH), 4.46 (s, 4 H, CH2), 4.28 (br s, 6 H, NH)
49.37 (CH2)
a 1H and 13C NMR data were obtained in acetone-d6.
b Mp 193–194 °C (MeOH). Anal. Calcd for C28H30N4O3: C, 71.47; H 6.43; N, 11.91. Found: C, 71.44; H, 6.48; N, 11.94.
+
+
MS (EI): m/z (%) = 469 (100, [M – H+]), 440 (35, [M – 2 CH3 ]), 427 (75, [M – 3 CH3 ]), 383 (20, [M – 2 Ac – H+]).
c 1H and 13C NMR data were obtained in DMSO-d6.
d Mp 198–199 °C (EtOH). Anal. Calcd for C28H32N4O3×2 HCl×H2O: C, 59.68; H, 6.44; N 9.94. Found: N, 59.44; C, 6.34; N, 9.51. MS (EI):
m/z (%) = 308 (27, [M – C9H13N2O+]), 150 (75, [H2NC6H4NHAc+]), 132 (100, [C6H5NHAc+]), 108 (70, [H2NC6H4NH+]), 43 (35, [C3H7]+).
e Mp 210–212 °C (MeOH). Anal. Calcd for C34H42N4O5: C, 69.60; H, 7.22; N, 9.55. Found: C, 69.57; H, 7.11; N, 9.45. MS (MALDI-TOF):
m/z = 587 (100, [M + H+]).
f Mp 159–160 °C (MeOH). Anal. Calcd for C29H33N5O4: C, 67.55; H, 6.45; N, 13.58. Found: C, 67.45; H, 6.37; N, 13.27.
g Anal. Calcd for C40H52N6O4: C, 70.56; H, 7.70; N, 12.34. Found: C, 71.24; H, 7.72; N, 12.16.
h Anal. Calcd for C34H46N4O5: C, 69.13; H, 7.85; N, 9.48. Found: C, 69.35; H, 7.88; N, 9.27.
i Mp 75–77 °C (MeOH–H2O). Anal. Calcd for C24H30N4O: C, 73.81; H, 7.74; N, 14.35. Found: C, 73.61; H, 7.93; N, 14.18.
Target diamine blocks 9 were produced by deprotecting cycles bearing hard and soft donor centers we treated
amines 8 with gaseous HCl in anhyd dichloromethane block 9b with various pyrrolic dialdehydes in methanol
(Scheme 5, Tables 1 and 2) followed by brief treatment (Scheme 6). Due to low activity of the starting diformyls
with 10% aqueous Na2CO3 solution. The above condi- 1c and 1e, an acid catalyst was required (vide supra) to
tions were found to be optimal due to high yields of the provide efficient macrocyclization. When 9b was treated
desired diamines 9. In addition, usual workup is actually with diformyldipyrrolylmethane 1e, the expected product
very simple and requires only evaporation of the solvents. 10a of 1:1 macrocyclization was isolated and character-
We observed that free amines 9 are prone to undergo ized by both 1H and 13C NMR and mass spectrometry. In-
spontaneous oxidation on contact with air. In view of the teresting results were obtained when diformylpyrrole 1c
above mentioned instability, target diamines 9 can be was introduced into the reaction with 9b. Thus, according
fixed in the form of stable dihydrochlorides if no treat- to MALDI-TOF spectra of the crude reaction mixture, no
ment with Na2CO3 is carried out at the stage of deprotect- peak corresponding to target macrocycle 10b10 was de-
ing amines 8.
tected, the main peak being due to unexpected 2:2-cyclo-
condensation product. We also observed that the above
product is an unstable compound which is prone to give
oligomers when attempts were made to isolate it in pure
form.
The final objective of our studies was to demonstrate the
possibility of using diamine blocks in creating macrocy-
clic Schiff bases. In order to obtain unsymmetrical macro-
R
R
N
N
NH HN
H
N
H
N
H
N
H
N
R
R
HN
HN
NH
NH
NH
HN
H2N
NH2
Boc
Boc
Boc
Boc
9
6
Boc
Boc
8
8
Scheme 4
Scheme 5
Synthesis 2007, No. 8, 1169–1174 © Thieme Stuttgart · New York

PAPER
Synthesis of Pincer-Type Heterodentate Azomethines
1173
50 °C. Then hexane was slowly added until the solution became
slightly turbid. Upon cooling, the precipitate which formed was fil-
tered out to give 40 g (69%) of 5.
1e or 1c
MeOH, acid
N
1H NMR (400 MHz, CDCl3): d = 1.53 (s, 9 H, t-C4H9), 3.81 (br s, 2
H, NH2), 6.36 (br s, 1 H, NH), 6.9–6.7 (m, 2 H, CH), 7.00 (td, 1 H,
J = 7.7, 1.5 Hz, CH), 7.28 (d, J = 7.6 Hz, CH).
N
NH
N
HN
N
NH
HN
13C NMR (100 MHz, DMSO-d6): d = 28.29 (CH3), 80.44 (C),
117.55 (CH), 119.56 (CH), 124.77 (CH), 126.07 (CH), 126.94 (C),
139.85 (C), 153.87 (C=O).
NH2
H2N
Y
10
9b
Scheme 6
Schiff Bases 6a–f; General Procedure
To a solution of 1a–g (1 mmol) in a minimum quantity of anhyd
MeOH (10–30 mL) was added 5 (416 mg, 2 mmol) (a few crystals
In summary, we have developed a simple and efficient
method of producing polyamines which can be utilized as of PTSA were also added when compounds 1c, 1e, and 1f were
loaded) and the mixture was stirred at r.t. The reaction was moni-
useful synthons for creating functionally substituted mac-
tored by analytical TLC (eluent EtOAc–petroleum ether, 1:1). After
rocycles. The key advantage of this approach is the small
filtration of the target compounds 6a–f, the filtrate was evaporated
to dryness and the precipitate so-obtained was purified by chroma-
tography on silica gel (EtOAc–petroleum ether, 1:1) to give addi-
number of stages (three) and good overall yields. Coupled
with availability of starting dicarbonyl compounds and
monoprotected diamine, it affords additional synthetic
benefits for constructing novel macrocycles. We are cur-
rently investigating the flexibility of this method to pre-
pare novel macrocyclic derivatives by means of varying
aromatic diamines and dicarbonyl components.
tional portions of 6a–f (Tables 1 and 2).
Protected Pincer-Type Ligands 8a–d; General Procedure
To a suspension of 6 (0.3 mmol) in anhyd MeOH (10 mL), was add-
ed NaBH4 (38 mg, 1.0 mmol) and mixture was stirred for 3 h. It was
then concentrated in vacuo, diluted with CH2Cl2 (25 mL), and fil-
tered through a short silica column. Evaporation of the solvents
gave the respective 8a–d (Tables 1 and 2).
1H and 13C NMR spectra were recorded on a Bruker Avance 400
MHz NMR spectrometer at 24 °C. IR spectra were determined on a
Nicolet FT-IR spectrometer. Mass spectra were performed on a
MALDI-TOF Reflex 3 instrument (Bruker) in the positive ion mode
(UV laser, 337 nm) and on a Finnigan MAT 212 instrument; the en-
ergy of ionizing electrons was 70 eV; the temperature of the ioniza-
tion chamber was 230 °C.
Pincer-Type Diamines 9a, 9b, 9d; General Procedure
Stream of dry HCl was bubbled through a solution of 8 (0.1 mmol)
in anhyd CH2Cl2 (20 mL). After 40 min, the precipitate formed was
treated with 10% aq solution of Na2CO3 to pH >7. The organic layer
was dried (K2CO3) for 6 h and solvent was removed under reduced
pressure to give the respective 9a, 9b, 9d (Tables 1 and 2).
The starting compounds were synthesized by literature methods:
1a,11 1b,12 1c,13 1d,14 1e,15 1g16 and N-acetyl-o-phenylenediamine.17
A sample of diformyl 1f was a gift from Mr. Nikolai V. Boev (M.
V. Lomonosov Moscow State University).
Macrocycle 10a; Typical Procedure
To a solution of 9b (32 mg, 0.1 mmol) and 1e (2.3 mg, 0.1 mmol)
in anhyd MeOH (10 mL), was added one drop of H3PO4 (70% aq).
After stirring overnight, anhyd Et3N (1 mL) was added and the pre-
cipitate was filtered out. The solvent and excess of Et3N were evap-
orated in vacuo and the residue was purified by flash
chromatography on alumina Brockmann grade II (elution with
CH2Cl2–MeOH, 95:5) to give 46 mg (90%) of 10a as a yellow pow-
der.
1H NMR (400 MHz, CDCl3): d = 10.01 (s, 2 H, NH), 7.72 (d,
J = 8.1 Hz, 2 H, CH), 7.3–7.0 (m, 6 H, CH), 6.84 (d, J = 7.6 Hz, 2
H, CH), 6.54 (br s, 2 H, CH), 6.14 (br s, 2 H, CH), 5.18 (s, 4 H, CH2),
1.72 (s, 6 H, CH3).
Schiff Base 3
To solution of N-acetyl-o-phenylenediamine (1.455 g, 9.7 mmol) in
anhyd MeOH (7 mL) was added dropwise a solution of 1a (1 g, 4.85
mmol) in anhyd MeOH (7 mL). The mixture was stirred for 8 h at
r.t. Product 3 was collected by filtration. An additional portion of
the substance was obtained by the partial evaporation of the filtrate
to give 2.24 g (98%) of 3 (Table 2).
Pincer-Type Amine 4
To a cooled (0 °C) solution of 3 (5.0 g, 10.65 mmol) in EtOH (150
mL) was added portionwise NaBH4 (1.62 g, 42.6 mmol) over 1.5 h.
The mixture was stirred for 2 d, and then treated with solution of
NaOH (3.5 g) in H2O (12.5 mL). The product was extracted with
CHCl3 (2 × 100 mL). The organic extracts were dried (Na2SO4) and
evaporated to dryness. The resulting oil was treated with a large ex-
cess of concd HCl (10 mL). Then the dihydrochloride salt of 4 was
purified by recrystallization from EtOH to give 4.23 g (84%) of pure
4·2HCl·H2O (Table 2).
13C NMR (400 MHz, CDCl3): d = 155.82 (C=N), 148.09 (C),
142.97 (C), 142.2 (C), 138.2 (C), 135.57 (C), 122.46 (CH), 120.77
(CH), 120.21 (CH), 119.35 (CH), 116.66 (CH), 113.27 (CH),
108.70 (CH), 106.36 (CH), 46.03 (CH2), 30.30 (C), 10.78 (CH3).
MALDI-TOF: m/z (%) = 510 (M – 3 H+, 100), 1024 [(M – H)2 , 10].
+
Acknowledgment
N-tert-Butoxycarbonyl-o-phenylenediamine (5)
The authors are grateful to Dr. Vsevolod Yu. Pavlov (M.V. Lomo-
nosov Moscow State University and M.V. Lomonosov Moscow
State Academy of Fine Chemical Technology) for interesting dis-
cussions and polishing the English text. We also thank Mr. Nikolai
V. Boev (M.V. Lomonosov Moscow State University) for helpful
discussion and for the gift of a sample of compound 1f. This work
was supported by Russian Foundation for Basic Research (grants
05-03-3684, 05-03-08017 and 06-03-81026).
To a solution of o-phenylenediamine (30 g, 278 mmol) in 1,4-diox-
ane (900 mL), H2O (60 mL), concd HCl (48 mL) and additional por-
tion of H2O (30 mL) were successively added. Then Boc2O (60.6 g,
278 mmol) was added and the solution was stirred at r.t. for 10 min.
Solid NaHCO3 (70 g, 834 mmol) was added and the solution was
thoroughly triturated and evaporated to dryness under reduced pres-
sure. The precipitate so-obtained was extracted with CHCl3 (300–
400 mL). NaCl was filtered out and the solution was brought to 40–
Synthesis 2007, No. 8, 1169–1174 © Thieme Stuttgart · New York

1174
N. E. Borisova et al.
PAPER
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Synthesis 2007, No. 8, 1169–1174 © Thieme Stuttgart · New York